The overall goal of this program project is to characterize the cellular and molecular basis of the immune pathogenesis of insulin-dependent diabetes mellitus (IDDM). The information obtained will be utilized to design a specific immune intervention strategy to prevent or treat IDDM. The program project involves a collaborative interaction between four departments. The grant is organized into four individual projects supported by three cores. The expertise of the project leaders bridge the disciplines of immunology, biochemistry, genetics, and pathology. The will use a wide range of techniques to characterize the immunologic and molecular perturbations, leading to the selective destruction of pancreatic beta cells. Project 1 will focus on the feasibility of islet- directed gene transfer to express several well characterized chemokines within islet allografts to promote local immunomodulation. Project 2 will investigate the intra-islet T-cell immunoregulatory events and the delineation of several putative autoimmune diabetes of NOD mice. Novel immune intervention strategies will be applied to treatment of diabetic NOD mice with islet transplantation. Project 3 will focus on the physical and metabolic characteristics of islet tissue to explore the technology of genetic engineering for modification of islet tissue prior to transplantation. Project 4 will focus efforts on characterizing the sphingomyelinase/ceramide and phospholipase A2 signal transduction pathways in mediating the effect of cytokine in the beta cell destruction. Core units for project administration, islet isolation, and vector preparation will provide necessary coordination and infrastructure for the program project. Collectively, this program project is an integrated and focused multidisciplinary effort to list the mechanisms that lead to the destruction of pancreatic beta cells in diabetes mellitus. The proposed studies are designed to elucidate the pathophysiology of IDDM and to utilize modern transplantation and molecular techniques to improve the treatment of the disease.